Review paper
Immunosenescence and late life depression

Introduction
Late-life depression has been defined as occurrence of depressive symptoms in people at age over 65 (International Statistical Classification of Diseases and Related Health Problems. 10th Revision. World Health Organization). There is some evidence that the prevalence of depressive symptoms increase with age and that most of depressed people do not receive medical treatment for their psychiatric conditions [1-2]. Depression violently affects health and shortens life span due to increased risk of cardiovascular events [3-15]. Immune response alterations and hypothalamic-pituitary-adrenocortical axis hyperactivity, have been suggested to cause cardiovascular pathology in depressed subjects [16]. Depression is also a predictor for mortality from cancer, respiratory diseases, neuropathologies, metabolic diseases and mental disorders [17-23]. Presence of one or more chronic physical diseases increases significantly the risk of comorbid depression. Comorbidity leads to health worsening compared with depression alone as well as chronic diseases alone and with any combination of them without depression [24]. Depressed patients represent lower health status than patients without depression [25-27]. The problem of depression has been shown in World Health Organization predictions. WHO expects depression to become the firs leading cause of disease burden by the year 2030, advancing from the second position in the former prognoses for 2020 [28-29]. There is a need for the extensive studies on mechanism involved in ethiopatogenesis of late-life depression to combat the growing medical, social and economic problem and successfully cure depression.

Oxidative damage and immune-inflammatory activation play a role in depression
There are evidences from depressed people including elderly that oxidative damage and immune-inflammatory activation play a role in depression and there is a need or extensive studies on links between this biological systems [30-33]. It has been reported that proinflammatory cytokines i.e. IL-1, IL-6, TNF-a enhance oxidative damages of DNA, expressed as increase of 8OH-dG [34- 35]. One of the theories proposed for aging is the Oxidative Theory of Aging [36]. Although this theory was put forth in 1956 and was widely supported [37-40], as well as relationship between systemic oxidative stress and unsuccessful aging [41], the role of free radicals in ethiopatogenesis of late-life depression had not been investigated for the long time. Even in the half 90s there were evidences for oxidative stress contribution in many diseases but authors did not mentioned depression [42-43]. Moreover only in 2006 there were first data on oxidative damage to DNA in clinical depression [44].
Much more research have been conducted to understand relation between depression and immune functions. The problem of how depression is related to immune system in elderly is complicated as immune system shows many age-dependent changes and there is a growing body of data concerning the complex process of immunosenescence.

Aging related low-grade inflammatory activity
Aging is associated with chronic, low-grade inflammatory activity and altered acute phase response [45-46]. In elderly subjects cytokine production shifts from Th1 to Th2. Interelukin IL-2 and interferon INF-gamma production decreases and IL-4 and IL-10 increases [47-51]. The balance between proinflammatory and anti-inflammatory cytokines response are crucial for successful aging. Increased production of proinflammatory cytokines and chemokines have been observed in healthy aged subjects as well as in old people with developed pathologies in most studies [45, 52-54]. Proinflammatory cytokines, TNF-a and IL-1b induce a second wave of cytokines including chemokines and IL-6 and further induces the synthesis of acute phase proteins [46].
Although elevated level of circulating inflammatory mediators was confirmed in age-related diseases the nature of direct role of inflammatory mediators remains to be unclear with indications on a positive feedback mechanism causing direct pathogenetic role of TNF-a and IL-6 [55]. Circulating level of TNF-a and IL-6 in elderly differs depending on progress of inflammatory diseases, and TNF-a is a marker of frailty in the very elderly whereas IL-6 do not affect survival in centenarians [56-57]. Increased soluble tumor necrosis factor receptor sTNF-R observed in the serum of elderly people may oppose the physiologic effects of TNF [58]. It has been hypothesized that association of an increased serum level of IL-8 and low level of IL-6 is related to longevity [59].

Inflammatory mediators in late-life depression
Increase in IL-1b, IL-6 and TNF-a has been reported in late-life depression [33, 60-63]. In regard to IL-1b, a high innate IL-1 receptor antagonist (IL-1ra) to IL-1b production capacity results in better ability to neutralize inflammation, have protective effect against depressive symptoms in elderly. Conversely low IL-1ra and high IL-1b productions add up to risk to develop depression via modulation of the HPA-axis activity and serotonin re-uptake stimulation. The question whether these cytokines originate from microglia cells in the brain or from the systemic inflammatory response, needs further research [63].

Immune functions in elderly
Increased level of serum immunoglobulins G, M and A [49-50, 52], alpha 2-macroglobulin [49] and memory T cells [49, 64] has been observed in elderly. On the contrary level of lymphocytes, T cells [49-50] and the titers of zinc [50] have decreased. Number of T cells decreases and the CD8 cells decreased more than the CD4 cells, resulting in
a increased CD4/CD 8 ratio. Moreover, lower number of naive (CD45RA+) and a higher number of memory (CD45R0+) were observed [49-50]. Decrease in number of B cells and specific antibodies is coupled with increase of unspecific immunoglobulins [49-50].
The main changes observed in neutrophils are increased activation coupled with diminished phagocytic capacity, depressed oxidative burst, reduction in chemotaxis and resistance in apoptosis [47, 50]. Higher number of neutrophils and monocytes has also been observed in depressed elderly [33].
Natural killer cell activity is also deteriorated with age and defects in their functional activity can be linked with decreased production of IL-8 and decreased production of superoxide in granulocytes [47, 50, 52, 65-66]. Late -life depression is associated with impaired peripheral immune efficiency [67].
Monocytes, basophils, eosinophils remain unchanged during aging [49-50]. C-reactive protein(CRP) has been also reported not age dependent [49, 68].
The relations of CRP to depression in general population has not been established however high concentration of CRP has been demonstrated in association with depressive symptoms in elderly people [63, 69-70].

Systemic inflammation and CNS function
There are evidences that systemic inflammation is related to local pathology in the CNS due to cytokines crossing the deteriorated blood-brain barrier and activation of hypothalamic-pituitary-adrenal axis [71-72]. Increased release of corticotropin-releasing hormones (CRH) in hypothalamic and extrahypothalamic sites may influence serotonin (5-HT) processes, and in consequence alter neuroplastic processes and lead to depression [73]. It has been also hypothesized that peripheral inflammation represents spillover from inflammatory processes in CNS [45]. Communication between peripheral immune activation and the brain is mediated by IL-1b, IL-6 and TNF-a [63, 74].

Brain-endocrine-immune response and zinc status in relation to depression
Altered immune response due to its interrelationship to brain and endocrine system can affect their functions which are pivotal for development of depressive symptoms. There are evidences that brain-endocrine-immune response in successful aging is correlated with metallothioneines (MTs) and therefore homeostasis of zinc. Zinc deficiency, even within the reference values, affects activity of antioxidant zinc-dependent enzymes, multiple aspects of innate and adaptive immunity and psychological dimensions in elderly [50, 75-80]. Immunomodulatory and antidepressant-like effect of zinc suplementation has been also confirmed [81-83].
MTs are induced by IL-6 and glucocorticoids to protect cells from reactive oxygen species and induce prompt immune response. Aging significantly disturbs this process as the functional role of MTs turn-off from dispensing to sequesting zinc due to constant inflammation and chronic oxidative stress. Increased level of MTmRNA in lymphocytes of elderly subject in comparison with young-adults and nonagenarians has been reported. In old mice high level of liver MTmRNA goes together with increased level of IL-6 and glucocorticoids, depressed IL-2, decreased NK cell activity and impaired capacity of poly(ADP-ribose) polymerasse-1 (PARP-1), low level of zinc ions bioavailability and loss of immune plasticity. Zinc deprivation and aging bear many similarities in immune functions alterations [50, 75, 79, 84-86].

Immune activation in late life depression has been also confirmed with data suggesting increased level of pterins in depressed elderly subject [87].
There is significant set of scientific data to describe changes in immune system during ageing but there is need for the extensive studies on immunosenescence in relation to oxidative stress and further on the links between immune dysregulation and oxidative stress in clinical depression [88].

References
1. Schoevers RA, Beekman AT, van Tilburg W (2000): Association of depression and gender with mortality in old age. Results from the Amsterdam Study of the Elderly (AMSTEL). Br J Psychiatry 177: 336-342.
2. Marcellini F, Giuli C, Papa R et al. (2006): Psychosocial aspects and zinc status: is there a relationship with successful aging? Rejuvenation Res 9: 333-337.
3. Murphy E, Smith R, Lindesay J, Slattery J (1988): Increased mortality rates in late-life depression. Br J Psychiatry 152: 347-353.
4. Schulz R, Beach SR, Ives DG et al. (2000): Association between depression and mortality in older adults: the cardiovascular health study. Arch Intern Med 160: 1761-1768.
5. Rozzini R, Sabatini T, Frisoni GB et al. (2002): Depressive symptoms and negative outcomes in older hospitalized patients. Arch Intern Med 162: 948-949.
6. Ryan J, Carriere I, Ritchie K et al. (2008): Late-life depression and mortality: influence of gender and antidepressant use. Br J Psychiatry 192: 12-18.
7. Wulsin LR, Vaillant GE, Wells VE (1999): A Systematic review of the mortality of depression. Psychosom Med 61: 6-17.
8. Barth J, Schumacher M, Herrmann C (2004): Depression as
a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med 66: 802-813.
9. Carney RM, Freedland KE, Miller GE, Jaffe AS (2002): Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res 53: 897-902.
10. Carney RM, Sheps DS (2004): Depression is a risk factor for mortality in coronary heart disease. Psychosom Med 66: 799-801.
11. Abas M, Hotopf M, Prince M (2002): Depression and mortality in a high-risk population. 11-Year follow-up of the medical research council elderly hypertension trial. Br J Psychiatry 181: 123-128.
12. Sable J, Dunn LB, Zisook S (2002): Late-life depression. How to identify its symptoms and provide effective treatment. Geriatrics 57: 18-35.
13. Lett HS, Blumenthal JA, Babyak MA et al. (2004): Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med 66: 305-315.
14. Rudisch B, Nemeroff CB (2003): Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 54: 227-240.
15. Musselman DL, Evans DL, Nemeroff CB (1998): The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 55: 580-592.
16. Joynt KE, Whellan DJ, O’Connor CM (2003): Depresssion and cardiovascular disease: mechanisms of interaction. Biol Psychiatry 54: 248-261.
17. Mykletun A, Bjerkeset O, Dewey M et al. (2007): Anxiety, Depression, and Cause-Specific Mortality: The HUNT Study. Psychosom Med 69: 323-331.
18. Eaton WW (2002): Epidemiologic evidence on the comorbidity of depression and diabetes. J Psychosom Res 53: 903-906.
19. Eaton WW, Armenian H, Gallo J et al. (1996): Depression and risk for onset of type II diabetes. A prospective population-based study. Diabetes Care 19: 1097-1102.
20. Penninx B, Guralnik J, Pahor M et al. (1998): Chronically depressed mood and cancer risk in older persons. J Natl Cancer Inst 90: 1888-1893.
21. Raison CL, Miller AH (2003): Depression in cancer: new developments regarding diagnosis and treatment. Biol Psychiatry 54: 283-294.
22. Spiegel D, Giese-Davis J (2003): Depression and cancer: mechanisms and disease progression. Biol Psychiatry 54: 269-282.
23. Larson SL, Owens PL, Ford D, Eaton W (2001): Depressive disorder, dysthymia, and risk of stroke: thirteen-year follow-up from the Baltimore epidemiologic catchment area study. Stroke 32: 1979-1983.
24. Moussavi SM, Chatterji SC, Verdes E et al. (2007): Depression, chronic diseases, and decrements in health: results from the World Health Survey. Lancet 370: 851-858.
25. Noel PH, Williams JW Jr, Unutzer J et al. (2004): Depression and comorbid illness in elderly primary care patients: impact on multiple domains of health status and well-being. Ann Fam Med 2: 555-562.
26. Kosloski K, Stull DE, Kercher K, Van Dussen DJ (2005): Longitudinal analysis of the reciprocal eff ects of self-assessed global health and depressive symptoms. J Gerontol B Psychol Sci Soc Sci 60: 296-303.
27. Katon W, Sullivan M, Russo J et al. (1993): Depressive symptoms and measures of disability: a prospective study. J Affect Disord 27: 245-254.
28. Global Burden of Disease 2004 Update: Selected figures and tables. World Health Organization 2008.
29. Summary: the global burden of disease. Boston: Harvard School of Public Health, 1996.
30. Forlenza MJ, Miller GE (2006): Increased Serum Levels of
8-Hydroxy-2’-Deoxyguanosine in Clinical Depression. Psychosom Med 68: 1-7.
31. Irie M, Miyata M, Kasai H (2005): Depression and possible cancer risk due to oxidative DNA damage. J Psych Res 39: 553-560.
32. Khanzode SD, Dakhale GN, Khanzode SS et al. (2003): Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors, Redox Rep 8: 365-370.
33. Dimopouls N, Piperi C, Psarra V et al. (2008): Increased plasma level of 8-iso-PGF2a and IL-6 in elderly population with depression. Psychiatry Research 161: 59-66.
34. Park YM, Han MY, Blackburn RV, Lee YJ (1998): Overexpression of HSP25 reduces the level of TNFalpha-induced oxidative DNA damage biomarker, 8-hydroxy-2’-deoxyguanosine, in L929 cells. J Cell Physiol 174: 27-34.
35. Ohtaki H, Takaki A, Yin L et al. (2003): Suppression of oxidative stress after transient focal ischemia in interleukin-1 knock out mice. Acta Neurochir 86 (Suppl): 191-194.
36. Harman D (1956): Aging: a theory based on free radical and radiation chemistry. J. Gerontol 11: 298-300.
37. Harman D (1992): Free radical theory of aging. Mutat Res 275: 257-266.
38. Beckman KB, Ames BN (1998): The free radical theory of aging matures. Physiol Rev 78: 547-581.
39. Finkel T, Holbrook NJ (2000): Oxidants, oxidative stress and the biology of aging. Nature 408: 239-247.
40. Melov S, Ravenscroft J, Malik S et al. (2000): Extension of life-span with superoxide dismutase/catalse mimetics. Science 289: 1567-1569.
41. Mezzetti A, Lapenna D, Romano F et al. (1996): Systemic oxidative stress and its relationship with age and illness. Associazione Medica “Sabin”. J Am Geriatr Soc 44: 823-827.
42. Harman D (1984): Free radical theory of aging: the free radical disease. Age 7: 111-131.
43. Martinez-Cayuela M (1995): Oxygen free radicals in human disease. Biochimie 77: 147-161.
44. Florenza MJ, Miller GE (2006): Increased serum levels of
8-hydroxy-2-deoxyguanosine in clinical depression. Psychosom Med 68: 1-7.
45. Bruunsgaard H, Pedersen M, Pedersen BK (2001): Ageing and proinflammatory cytokines. Curr Opin Hematol 8: 131-136.
46. Bruunsgaard H (2006): The clinical impact of systemic low-level inflammation in elderly populations. with special reference to cardiovascular disease, dementia and mortality. Danish Medical Bulletin 3: 285-309.
47. Gindali L. De Martinis M, D’Ostilio A et al. (1999): The immune system in elderly. Immunol Res 20: 117-126.
48. Alberti S, Cavenini E, Ostan R et al. (2006): Age-dependent modifications of Type 1 and Type 2 cytokines within virgin and memory CD4+ T cells in humans. Mech Ageing Dev 127: 560-566.
49. Rink L, Seyfarth M (1997): Characteristics of immunological test values in the elderly. Z Gerontol Geriatr 30: 220-225.
50. Haase H, Rink L (2009): The immune system and the impact of zinc during aging. Immun Ageing 6: 9.
51. Esumi E, Araga S, Takahashi K (2009): Serum interleukin-2 levels in patients with dementia of the Alzheimer type. Acta Neurologica Scandinavica 84: 65-67.
52. Sirnivasan V, Maestroni GJ, Cardinali DP et al. (2005): Melatonin, immune function and aging. Immun Ageing 2: 17.
53. Mariani E, Cattini L, Neri S et al. (2006): Simultaneous evaluation of circulating chemokine and cytokine profiles in elderly subjects by multiplex technology: relationship with zinc status. Biogerentology 7: 449-459.
54. Csiszar A, Ungvari Z, Koller A et al. (2003): Aging-induced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J 17: 1183-1185.
55. Krabbe KS, Pedersen M, Bruunsgaard H (2004): Inflammatory mediators in the elderly. Exp Gerontol 39: 687-699.
56. Bruunsgaard H, Pedersen BK (2003): Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 23: 15-39.
57. Bruunsgaard H, Andersen-Ranberg K, Hjelmborg J et al. (2003): Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med 115: 278-283.
58. Hasegawa Y, Sawada M, Ozaki N et al. (2000): Increased Soluble tumor necrosis factor receptor levels in the serum of elderly people. Gerontology 46: 185-188.
59. Wieczorkowska-Tobis K, Niemir ZI, Podkówka R et al. (2006): Can increased level of circulating IL-8 be a predictor of human longevity? Med Sci Monit 12: 118-121.
60. Pennix BW, Kritchevsky SB, Yaffe K et al. (1999): Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition Study. Biol Psychiatry 46: 1649-1655.
61. Thomas AJ, Davis S, Morris C et al. (2005): Increase in interleukin-1b in late-life depression. Am J Psychiatry 162: 172-177.
62. Tiemeier H, Hofman Albert, van Tuijl HR et al. (2003): Inflammatory proteins and depression in the elderly. Epidemiology 14: 103-107.
63. van den Biggelaar AHJ, Gussekloo J, de Craen AJM et al. (2007): Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age. Exp Gerontol 42: 693-701.
64. Karanfilov CI, Liu B, Fox CC et al. (1999): Age-related defects in Th1 and Th2 cytokine production by human T cells can be dissociate from altered frequencies of CD45RA+ and CD45RO+ T cell subsets. Mech Ageing Dev 109: 97-112.
65. Mariani E, Pulsatelli L, Meneghetti A et al. (2001): Different IL-8 production by T and NK lymphocytes in elderly subjects. Mech Ageing Dev 122: 1383-1395.
66. Solana R, Mariani E 2000: NK and NK/T cells in human senescence. Vaccine 18: 1613-1620.
67. Tsuboi H, Kawamura N, Hori R et al. (2005): Depressive symptoms and life satisfaction in elderly women are associated with natural killer cell number and cytotoxicity. Int J Behav 12: 236-243.
68. Evrin PE, Nilsson SE, Oberg T, Malmberg B (2005): Serum C-reactive protein in elderly men and women: association with mortality, morbidity and various biochemical values. Scand
J Clin Lab Invest 65: 23-31.
69. Kuo H-K, Yen C-J, Chang C-H et al. (2005): Relation of
C-reactive protein to stroke, cognitive disorders, and depression in the general population: systematic review and meta-analysis. Lancet Neurol 4: 371-380.
70. Ross R (1999): Atherosclerosis is an inflammatory disease. Am Heart J 138: 419-420.
71. Garton MJ, Keir G, Lakshmi MV, Thompson EJ (1991): Age-related changes in cerebrospinal fluid protein concentrations. J Neurol Sci 104: 74-80.
72. Tracey KJ (2002): The inflammatory reflex. Nature 420: 853-859.
73. Anisman H (2009): Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. J Psychiatry Neurosci 34: 4-20.
74. Schulte-Herbrüggena O, Nassensteinb C, Lommatzschc M et al. (2005): Tumor necrosis factor-a and interleukin-6 regulate secretion of brain-derived neurotrophic factor in human monocytes. J Neuroimmunol 160: 204-209.
75. Giacconi R, Cipriano C, Muzzioli M et al. (2003): Interrelationships among brain, endocrine and immune response in ageing and successful ageing: role of metallothionein III isoform. Mech Ageing Dev 124: 371-378.
76. Marcellini F, Giuli C, Papa R et al. (2007): Psychological and biochemical interactions in aging: preliminary results from an Italian old sample of “ZINCAGE” project. Arch Gerontol Geriatr 1 (Suppl): 259-269.
77. Beltramini M, Di Pisa C, Zambenedetti P et al. (2004): Zn and Cu alteration in connection with astrocyte metallothionein I/II overexpression in the mouse brain upon physical stress. Glia 47: 30-34.
78. Marcellini F, Giuli C, Papa R et al. (2006): Zinc status, psychological and nutritional assessment on old people recruited in five European countries: Zincage study. Biogerontology 7: 339-345.
79. Haase H, Moccheigani E, Rink L (2006): Correlation between zinc status and immune function in the elderly. Biogerontology 7: 421-428.
80. Varin A, Larbi A, Dedoussis GV et al. (2008): In vitro and in vivo effects of zinc on cytokine signalling in human T cells. Exp Gerontol 43: 472-482.
81. Mocchegiani E, Giacconi R, Costarelli L et al. (2008): Zinc deficiency and IL-6-174G/C polymorphism in old people from different European countries: effect of zinc supplementation. ZINCAGE study. Exp Gerontol 43: 433-444.
82. Marcellini F, Giuli C, Papa R et al. (2008): Zinc in elderly people: effects of zinc supplementation on psychological dimensions in dependence of IL-6-174 polymorphism:
a Zincage study. Rejuvenation Res 11: 479-483.
83. Franco JL, Posser T, Brocardo PS et al. (2008): Involvement of glutathione, ERK 1/2 phosphorylation and BDNF expression in the antidepressant-like effect of zinc in rats. Behavioural Brain Research 188: 316-323.
84. Mocchegiani E, Giacconi R, Cipriano C et al. (2002): MtmRNA gene expression, via IL-6 and glucocorticoids, as potential genetic marker of immunosenescence: lesson from very old mice and humans. Exp Gerontol 37: 349-357.
85. Mocchegiani E, Muzzioli M, Giacconi R et al. (2003): Metallothioneines/PARP-1/IL-6 interplay on natural killer cell activity in elderly: parallelism with nonagenarians and old infected humans. Effect of zinc supply. Mech Ageing Dev 124: 459-468.
86. Mocchegiani E, Giacconi R, Cipriano C et al. (2002): Metallothioneines (I+II) and thyroid-thymus axis efficiency in old mice: role of corticosterone and zinc supply. Mech Ageing Dev 123: 675-694.
87. Tiemeier H, Fekkes D, Hofman A et al. (2006): Plasma pterins and folate in late life depression: The Rotterdam Study. Psychiatry Res 145: 199-206.
88. Forlenza MJ, Miller GE (2006): Increased Serum Levels of
8-Hydroxy-2’-Deoxyguanosine in Clinical Depression. Psychosom Med 68: 1-7.